Attenuated heart rate (HR) response during exercise is associated with adverse cardiovascular outcome. The acceptable value for HR response is 85% of the age-predicted maximal HR (APMHR). This study hypothesized that mild attenuation of HR response during exercise among healthy subjects is associated with increased cardiovascular risk. The study population comprised 10,323 healthy men and women without known cardiovascular disease (CVD) or diabetes mellitus who underwent a yearly screening program and were followed up during a mean period of 4.3 years. Participants were grouped to 3 tertiles based on the percentage of their APMHR reached at the baseline stress test. The primary end point was the occurrence of CVD or cerebrovascular disease. A total of 1,015 incident cases of CVD occurred during follow-up. A multivariate Cox proportional hazards regression model showed that the CVD risk of subjects who reached 60% to 96% of their APMHR was 35% greater compared with those who reached their APMHR (p = 0.001). A subgroup analysis among subjects who reached 85% of their APMHR showed that even mildly attenuated heart response (in the range of 85% to 96% APMHR) was independently associated with 36% increase in CVD risk (p <0.001). In conclusion, attenuated HR response during exercise is a powerful and independent predictor of adverse cardiovascular events during long-term follow-up among healthy men and women. The prognostic implications of attenuated HR response in this population are apparent even with a minor decrease of the maximal HR to <96% of the APMHR.